Characterization of insulin-resistance: role of receptor alteration in insulin-dependent diabetes mellitus, essential hypertension and cardiac hypertrophy

• Published in: European journal of pharmaceutical sciences 2000-10, Vol.11 (4), p.299-306
• Main Authors: Bikhazi, Anwar B., Azar, Sami T., Birbari, Adel E., El-Zein, Ghina N., Haddad, George E., Haddad, Raja E., Bitar, Khalil M.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Associated diseases and complications; Biological and medical sciences; Cardiomegaly - metabolism; Cell receptors; Cell structures and functions; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Essential hypertension; Female; Fundamental and applied biological sciences. Psychology; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Hypertension - metabolism; IDDM; Insulin - metabolism; Insulin binding; Insulin receptor alterations; Insulin resistance; Insulin Resistance - physiology; Insulin-Like Growth Factor I - metabolism; Male; Medical sciences; Molecular and cellular biology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, IGF Type 1 - metabolism; Species Specificity; Streptozocin
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/S0928-0987(00)00110-X

Insulin-resistance is associated with a number of disease states such as diabetes, syndrome X, and hypertension. These situations may be coupled to insulin-resistance through the insulin signaling system as a common pathway. The purpose of this study was to investigate the receptor binding alterations in streptozotocin-induced diabetic rats, spontaneously hypertensive rats and aortocaval shunted rats (eccentric cardiac hypertrophy). A physical model describing a 1:1 stoichiometry of ligand binding with its receptor is proposed describing reversible binding of [ 125I]insulin or [ 125I]IGF-1 at the microvascular endothelial as well as with the cardiac myocytes after CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function which allowed the calculation of the forward binding constants ( k n ), the reversible constants ( k − n ), the dissociation constants ( k d) and the residency time constants ( τ). The results showed that streptozotocin-induced diabetic rats showed insulin-resistance through alterations in the kinetics of insulin receptor binding. The normotensive controls of the spontaneously hypertension rats (SHR) carry themselves insulin-resistant receptors whose binding to insulin worsens in the hypertensive SHR. Negative cooperativity between insulin-like growth factor IGF-1 and insulin receptors could be a causative factor predisposing for insulin-resistance in the aortocaval shunted rats to insulin resistance. The defects may be occurring at the receptor level in insulin-dependent diabetes mellitus, Wistar-Kyoto rats and spontaneously hypertensive rats. In conclusion, alterations in the kinetics of insulin binding to its receptor seem to play a central role for the initiation of insulin-resistance during the various pathophysiological states.